Dengue Vaccine (CYD-TDV Dengvaxia )

Transcription

1 Dengue Vaccine (CYD-TDV Dengvaxia ) Annelies Wilder-Smith Consultant, Vaccines for Arboviral Diseases, WHO-IVB Lee Kong Chian School of Medicine, Singapore Director, Partnership for Dengue Control, Fondation Merieux SAGE meeting April

2 Dengue Rapidly expanding arboviral disease transmitted by Aedes mosquitoes 50 fold increase in past 50 years Four antigenically distinct serotypes (DENV1-4) Clinical spectrum: 80% asymptomatic Self-limiting febrile illness Severe dengue (~2-4% of symptomatic) Secondary infections are associated with higher risk of more severe dengue CFR 0.1 1% 1 st infection 2nd Primary infection Secondary 3 rd infection Death Tertiary Severe Dengue Symptomatic Asymptomatic 4th infection Flasche et al, PLoS Med.2016 Quaternary Slide 2

3 Dengue Vaccine ( Phase I Phase II Phase IIb Phase III Registration DPIV GlaxoSmithKline, Biomanguinhos, WRAIR TV003/TV005 US National Institutes of Health 1 Butantan CYD-TDV Dengvaxia Sanofi Pasteur DEN-80E Merck DENVax Takeda TVDV Naval Medical Research Center TLAV-TPIV WRAIR Live attenuated (recombinant) Heterologous Prime-Boost DNA Inactivated Subunit

4 Homotypic and heterotypic antibodies Anderson et al, A Shorter Time Interval Between First and Second Dengue Infections Is Associated With Protection From Clinical Illness in a School-based Cohort in Thailand. J Inf Dis Slide 4

5 Status of CYD-TDV (as of May 2018) Licensed by 20 countries Asia, Latin America, Australia Indication varies Typically 9-45 years Singapore (12-45 year-olds), Indonesia (9-16 year-olds) and Paraguay (9-60 yearolds) Vaccine introduction in public health programmes in two countries Philippines: Routine, school-based programme - 4 th grade children (9-10 year olds) in highly endemic regions (~1,000,000 children) programme suspended. Brazil: Paraná State about 500,000 doses in 30 most highly endemic municipalities (28 municip. age 15-27y, 2 municip. age 9-44y.) 5

6 Phase 3 Trials of CYD-TDV Included >30,000 children aged 2-16 years in 10 endemic countries in Asia and Latin America Adapted from Guy (2015) 6

7 VE against Symptomatic, Severe and Hospitalized Dengue (ITT) (M0-M25) Outcome Cases in Vaccine group (n) Symptomatic VCD Cases in Placebo group (n) Hospitalized VCD (15%) Severe VCD (4.5%) Pooled (2-16 years) 60.3% ( ) 72.7% ( ) 79.1% ( ) Pooled (9-16 years) 65.6% ( ) 80.8% ( ) 93.2% ( ) 7

8 Longer-term Follow Up for Hospitalized Dengue: 2-5 year age group Time Period (Follow up) CYD group cases CYD14 (2-5 years) Control group cases Year 1 (Active) 8 6 Year 2 (Active) 9 7 Year 3 (Hospital) 15 1 Year 4 (Hospital) 20 7 Year 5 (Hospital/SEP) 6 2 Cumulative Years RR (95%CI) 0.64 ( ) 0.64 ( ) 7.45 ( ) 1.42 ( ) 1.49 ( ) 1.26 ( ) 8

9 Conclusions and basis for SAGE recommendations in 2016 Unclear whether safety signal in 2-5 years olds was due to age or to a higher proportion of this age group being seronegative at vaccination, or both. Modelling of public health impact of the vaccine suggested most efficient to use when the target population had seroprevalence 70% or greater. Question remained as to whether vaccinated seronegatives 9y+ might be at increased risk of severe disease. This was highlighted as an important unanswered question by both GACVS and SAGE. Long-term prospective studies were thought to be needed to address the safety question However, in 2017, Sanofi Pasteur utilised a new assay on sera collected at month 13 (post-dose 3), which was designed to be able identify those who were seronegative at the time of vaccination (i.e. was not affected by the vaccine). 9

10 Study design overview (CYD14 & 15) Preliminary data available to Oct/Nov 2015* End of follow-up 2017/18 Vaccine doses Month ~48 72 Randomized CYD:Placebo 2:1 per protocol (PP) intention to treat (ITT) ACTIVE SURVEILLANCE HOSPITAL SURVEILLANCE ONLY SURVEILLANCE EXPANSION (ACTIVE SURV. RESTARTED) 10

11 Vaccine efficacy against symptomatic VCD in the 25 months after dose 1 (2-16 year-olds - MI method) Serostatus at dose 1 Vaccine efficacy 95% confidence interval Sero-positive 72% 58%, 82% Sero-negative 32% -9%, 58% 11

12 Relative risk of hospitalised VCD comparing vaccinated to controls in the 66 months after dose 1 (2-16 year-olds - MI method) Sero-status at dose 1 Relative risk (CYD:Control) 95% confidence interval Sero-positive , 0.42 Sero-negative ,

13 Relative risk of severe VCD comparing vaccinated to controls in the 66 months after dose 1 (2-16 year-olds - MI method) Sero-status at dose 1 Relative risk (CYD:Control) 95% confidence interval Sero-positive , 0.52 Sero-negative ,

14 Relative risk of hospitalised VCD and severe VCD in seronegatives in the 66 months after dose 1, comparing vaccinated to controls (MI method) Age Group (years) Hospitalised dengue Severe dengue

15 Explanatory hypothesis: Silent infection mode of action Vaccination primes the immune system similarly to infection: 1. Temporary high degree of cross-immunity in at least seronegative recipients 2. Seronegative recipients have secondary-like breakthrough infection once crossimmunity wanes 3. Seropositive recipients have tertiary-like breakthrough infection once crossimmunity wane 15 Ferguson et al., Science 2016; Flasche et al., PLoS Med. 2016

16 Time to hospitalized VCD MI method - age 9-16 years Cumulative % hospitalised VCD Sero +ve placebo Sero -ve CYD Sero -ve placebo Sero +ve CYD 16

17 Benefit-risk assessment Incidence rates (IRs) and attributable risks (ARs) in <9y and 9+y age groups (MI method) 17

18 Considerations A number of dimensions: Population benefit versus individual risk Ethical considerations Risk perceptions and communication Screening tests versus serosurveys Programmatic issues Vaccine coverage estimates Came down to an evaluation of: Population Seroprevalence Criteria without Screening Pre-Vaccination Screening SAGE 18 April 2018

19 1. Benefits and Harm Population Seroprevalence Criteria without Screening BENEFIT Overall substantial population benefit in areas with high seroprevalence predicted. HARM An identifiable subset of the population will be put at increased risk of severe dengue, at least in the short to medium term. Pre-Vaccination Screening BENEFIT Maximizing the benefit (high efficacy and good safety) in seropositive while avoiding harm in correctly identified seronegatives. HARM Some seronegative individuals will be put at increased risk of severe dengue if vaccinated due to a false positive screening test result. SAGE 18 April 2018

20 3. Population eligible for vaccination Population Seroprevalence Criteria without Screening Subnational areas with seroprevalence >80% in 9 year olds are predicted by modelling to be rare, those with seroprevalence >90% by the age of 9y very rare. Pre-Vaccination Screening Modelling predicts vaccine eligibility will be higher on a population basis compared to the seroprevalence criteria strategy, as all seropositive persons in the population are eligible. Strategy can be used in both high and moderate transmission settings, although pre-test probability will be higher in high transmission settings. SAGE 18 April 2018

21 4. Risk perception Population Seroprevalence Criteria without Screening Loss in vaccine confidence (dengue vaccines and possibly other vaccines). Inability of vaccinees to know own serostatus may lead to increased vaccine hesitancy. Pre-Vaccination Screening Risk of false positive test: seronegative individuals will be misclassified as seropositive and unintentionally vaccinated as no test will be 100% specific. SAGE 18 April 2018

22 5. Implementation challenges Population Seroprevalence Criteria without Screening Dengue transmission exhibits a high spatiotemporal heterogeneity. To identify subnational areas with seroprevalence above 80% by age 9 years, multiple smallscale age-stratified seroprevalence studies need to be conducted.. Providing appropriate information to those eligible for vaccination of the potential risks and benefits will be more challenging than for other vaccines. Pre-Vaccination Screening Pre-vaccination blood sampling may lead to decreased acceptance of the vaccination programme No rapid diagnostic test (RDT) has been validated or licensed for the indication of screening for past dengue infection. Unlikely that any test will have a 100% specificity, thereby still putting some truly seronegatives at risk. Tests with high sensitivity are needed to ensure that a large proportion of seropositives will benefit from CYD-TDV. SAGE 18 April 2018

23 2. % vaccinated at increased risk of severe dengue Population Seroprevalence Criteria without Screening Dependent on seroprevalence criteria chosen If vaccine is introduced in a setting with 80% seroprevalence, 20% of the vaccinated population will be put at risk. Pre-Vaccination Screening Dependent on the specificity of the screening test. In a setting with 80% seroprevalence and a test with 80% specificity, 20% of true seronegatives will be unintentionally vaccinated. That is, 4% of the total population would be unintentionally vaccinated. In a setting with 80% seroprevalence and a test with 98% specificity, 0.4% of the population would be unintentionally vaccinated. SAGE 18 April 2018

24 6. Population impact Population Seroprevalence Criteria without Screening Given that areas with seroprevalence above 80% by age 9y are predicted to be rare, population impact is likely to be low. Pre-Vaccination Screening Population impact on reduction of hospitalized dengue modelled at approximately 20% over 30 years. SAGE 18 April 2018

25 Recommendation Pre-Vaccination Screening For countries considering vaccination as part of their dengue control program, a pre-vaccination screening strategy would be the preferred option, in which only dengue-seropositive persons are vaccinated SAGE 18 April 2018